The effective treatment of organ-specific inflammatory disorders of putative autoimmune origin is an ongoing goal in clinical medicine. To date, clinically oriented approaches have centered on the administration of pharmacologic substances that have a non-specific effect on the immune response. More recently, cyclosporine, an undecapeptide which suppresses immune response nonspecifically with respect to the antigen but which has a predominantly anti-T cell mode of action (Nussenblatt, R. B., and A. G. Palestine, Surv. Ophthalmol. 31:159, 1986) has been successfully used for the treatment of several disorders of presumed autoimmune origin, including uveitis (Nussenblatt R. B., et al., Am. J. Ophthalmol. 96:275, 1983). Unfortunately, cyclosporine has serious side effects which limit its usefulness. Furthermore, as with all present immunosuppressant therapies, the medication effects associated with cyclosporine are non-specific.
Experimental immuno-therapeutic approaches to suppression of autoimmune diseases including uveitis have focused on the manipulation of the immune response by non-pharmacologic means, such as monoclonal antibody therapy (Hafler D. A., et al., J. Immunol. 141:131, 1988); T-cell vaccination (Ben-Nun, A., et al., Nature 292:60, 1981); and the induction of immune tolerance by feeding of autoantigens. Recently, feeding myelin basic protein (MBP), or its fragments, has been shown to prevent the histological and clinical expression of experimental autoimmune encephalomyelitis (EAE), which has been used as a model for the human demyelinating disease, multiple sclerosis (Higgins, P. J., and H. L. Weiner, J. Immunol. 140:440, 1988; Lider, et al., J. Immunol. 142:748, 1989; Bitar, D. M., and C. C. Whitacre, Cell Immunol. 112:364, 1988).
Experimental autoimmune uveoretinitis (EAU) can be induced by several autoantigens derived from the retina (Gery, I., et al., in N. Osborne and J. Chader (eds): Progress in Retinal Research. Oxford, Pergamon Press, vol. 5, pp 75-109, 1986). To date, the most evaluated antigen and model system is that induced by the retinal S-antigen (S-Ag) (Gery, I., et al., in Progress in Retinal Research, supra). It is believed that S-Ag is involved in actual uveoretinitis in man because afflicted humans are sensitized to S-Ag. The S-Ag model shows EAU to be a T-cell mediated disorder, with administration of long-term CD4+ T-cell lines specific for S-Ag capable of inducing the disorder (Caspi R. R., et al., J. Immunol. 136:928, 1986).
The S-Ag EAU model is of particular interest for several reasons. First, to date, S-Ag is the only retinal autoantigen to which a substantial number of patients with endogenous intermediate and posterior uveitis consistently demonstrate in vitro proliferative responses (Nussenblatt, R. B., et al., Am. J. Ophthalmol. 89:173, 1980; Nussenblatt, et al., Am. J. Ophthalmol. 94:147, 1982). Second, the entire amino acid sequence of S-Ag has recently been reported, with two fragments designated N and M, respectively, demonstrating uveitogenicity (Donoso, L. A., et al., Curr. Eye Res. 8:1151, 1987; Singh, V. K., et al., Cell. Immunol. 115:413, 1988). Third, immune manipulation of this model appears to have excellent predictive value for the human uveoretinitis, as was demonstrated with the clinical effectiveness of cyclosporine use in humans (Nussenblatt, R. B., et al., J. Clin. Invest. 67:1228, 1981) which was first tested on the EAU model.
An important goal of the present invention is to provide a more specifically focused or directed therapy against uveitis. A more particular goal of this invention is to provide a method for suppressing the symptoms of uveoretinitis by oral or enteral administration of agents that are directed at diminishing the immune response to uveitis-specific antigens.